Aromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide

ABSTRACT

This invention relates to aromatic 2-aminoalkyl derivatives of 1,2-benzoisothiazol-3(2H)one-1,1-dioxides, processes for the preparation of same, and to their use as anxiolytic and antihypertensive agents.

This is a divisional of application Ser. No. 158,432, filed Feb. 22,1988, now U.S. Pat. No. 4,789,676, which is a divisional of applicationSer. No. 836,276, filed Mar. 5, 1986, now U.S. Pat. No. 4,748,182,issued May 31, 1988.

FIELD OF THE INVENTION

This invention relates to certain aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivatives andtheir use as anxiolytic agents and antihypertensive agents.

BACKGROUND OF THE INVENTION

Anxiety has been defined as an apprehension or concern regarding somefuture event. Most, if not all, people occasionally suffer some symptomsof anxiety in response to appropriate stimuli. In some individuals,these feelings of anxiety or panic in response to the everyday pressuresof life can be overwhelming, rendering the individual an unproductivemember of society. Whereas individual group counseling represents thepreferred primary mode of therapy, the use of chemotherapeutic agentshas proven to be a useful adjunct in the treatment of anxiety, therebyenabling a seriously afflicted individual to regain protective statuswhile undergoing concurrent psychotherapy.

Compounds of the class of benzodiazepines are currently the therapeuticagents of choice in the treatment of anxiety. In particular,chlordiazepoxide, diazepam and oxazepam are commonly used. This class ofcompounds has a great potential for misuse, particularly among the classof patients undergoing therapy. Moreover, the benzodiazepines generallypossess desired sedative effects and process detracting interactionswith other drugs, including for example, alcohol.

Applicants have now discovered a class of novel aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide antianxiety agentsthat are generally free from the undesirable effects of thebenzodiazepines. The compounds disclosed herein, when practised inaccordance with the teachings of this invention help to alleviate suchsymptoms as excessive fear, worry, restlessness, tension, stress,neurotic depression and are useful in the relief of some personalitydisorders. Additionally, the compounds of this invention are effectiveantihypertensive agents which have the effect of lowering blood pressurein patients in need thereof.

SUMMARY OF THE INVENTION

This invention is directed to a class of aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivatives havingthe general formula ##STR1## wherein X is selected from the groupconsisting of ##STR2## n is an integer of from 2 to 5; A and B are eachoxygen, sulfur or NR' where R' represents hydrogen or methyl; R₁ ishydrogen, hydroxy or methoxy; R₂ is hydrogen or methyl; and thepharmaceutically acceptable acid addition salts thereof.

This invention also discloses a process for the preparation of thesecompounds and discloses their use as anxiolytic and antihypertensiveagents.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term "pharmaceutically acceptable acid additionsalts" is intended to apply to any non-toxic organic or inorganic acidaddition salts of the base compounds represented by Formula I.Illustrative inorganic acids which form suitable salts includehydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metalsalts such as sodium monohydrogen orthophosphate and potassium hydrogensulfate. Illustrative organic acids which form suitable salts includethe mono, di and tricarboxylic acids. Illustrative of such acids are,for example, acetic, glycolic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, p-hydroxybenzoic, phenylacetic, cinnamic,salicylic, 2-phenoxybenzoic acids, and sulfonic acids such asmethanesulfonic acid or 2-hydroxyethanesulfonic acid. Either the mono orthe di-acid salts can be formed, and such salts can exist in either ahydrated or a substantially anhydrous form. In general, the acidaddition salts of these compounds are crystalline materials which aresoluble in water and in various hydrophilic organic solvents.Additionally, in comparison to their free base forms, such saltsgenerally demonstrate higher melting points and an increased chemicalstability.

Specific subclasses of compounds that fall within the scope of thepresent invention are illustrated as follows: ##STR3##

A preferred subclass of this invention consists of those compounds offormula (1h) wherein the alkyl chain is terminally substituted with a(substituted)-1,2,3,4-tetrahydro-β-carboline ring system.

A more preferred subclass of this invention relates to those compoundsof formula (1f) wherein the alkyl chain is terminally substituted by the2,3-dihydronaphtho[1,2b][(1,4]-dioxin-2-yl or 3-yl ring system.

The most preferred compounds of this invention relate to those compoundsof formula (1a) wherein the alkyl chain is terminally substituted by the2,3-dihydro-1,4-benzodioxin-2-yl ring system.

The alkylene group depicted above --(CH₂)_(n) --, can be considered as aconnecting bridge which separates the two terminal heterocyclic ringsystems. As indicated, the symbol n can represent an integer of from 2to 5. Those alkylene groups in which n is from 2 to 4 represent thepreferred groups of this invention.

The aromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxidederivatives of formula (1) can be prepared in an analogous manner bystandard techniques known to those skilled in the art. Thus, thecompounds of this invention can be prepared via a condensation of theappropriate nucleophilic amine of formula (2) and with anN-alkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide substrate of formula(3) as indicated below ##STR4## wherein X and n are as defined informula (1) and the symbol (L) represents a suitable leaving group, suchas chlorine, bromine, iodine, a mesylate or tosylate.

Such a nucleophilic condensation is preferably conducted by reactingapproximately equimolar amounts of the nucleophile (2) with thesubstrate (3), for a period of from about 1 hour to 24 hours dependingupon the particular reactants employed. The reaction temperature canrange from about 25° C. to 140° C. Preferably the reaction is conductedat a temperature ranging from 60° C. to 125° C.

Additionally, the reaction is preferably conducted in the presence of atertiary organic base, such as a trialkylamine or pyridine, or on thepresence of an inorganic base such as potassium carbonate.

Inasmuch as the reactants employed are typically crystalline materials,the use of solvents is preferred. Suitable solvents include anynon-reactive solvent, preferably those having a boiling point in therange of from 60° C. to 150° C. Thus, for example, solvents such aspetroleum ethers; chlorinated hydrocarbons such as carbon tetrachloride,ethylene chloride, methylene chloride or chloroform; chlorinatedaromatic compounds such as 1,2,4-trichlorobenzene, or o-dichlorobenzene;carbon disulfide; ethereal solvents such as diethylether,tetrahydrofuran or p-dioxane; aromatic solvents, such as benzene,toluene or xylene; or an alcoholic solvent such as ethanol, can besuitably employed. Especially preferred solvents are those which areknown to promote nucleophilic reactions, such as dimethysulfoxide anddimethylformamide.

The products of formula (1) can be isolated utilizing appropriatetechniques available to those skilled in the art. Thus, for example, thereaction mixture can be filtered to remove solid materials, and thefiltrate subsequently evaporated to recover the active ingredient. Thecompounds of formula (1) can be further purified via recrystallizationor by forming and utilizing their picric or oxalic acid complexes.

The nucleophilic primary amines indicated by formula (2) are compoundswhich are either commercially available or which have been previouslydescribed in the literature. Alternatively, the primary amines,designated by the symbol X, wherein R₂ is hydrogen, can be readilyprepared via a reduction of the corresponding cyano derivatives. Thus,for example, compounds of formula (2), wherein X represents the radical##STR5## in which A and B are as defined in formula (1) above, areprepared by a reduction of the corresponding cyano derivative (4) shownbelow ##STR6##

Such a reduction can be accomplished utilizing a variety of reagentsystems, as for example, catalytic reductions employing hydrogen gaswith a catalytic metal such as palladium on charcoal, Raney nickel,platinum, rhodium, ruthenium or platinum oxide. In addition, reagentssuch as diborane, sodium borohydride, dissolving metal reductionsutilizing lithium, sodium, potassium, calcium, zinc, magnesium, tin oriron in liquid ammonia or a low-molecular weight aliphatic amine orsodium, aluminum or zinc amalgam, zinc, tin or iron in a hydroxylicsolvent or in the presence of an aqueous mineral acid, or lithiumaluminum hydride can be favorably employed.

The formula (2) nucleophiles wherein X represents the radical ##STR7##can be prepared by reacting the corresponding cyano compounds with from1 to 2 molar equivalents of lithium aluminum hydride in an appropriatesolvent. Preferably, about 1.5 molar equivalents of hydride areemployed. The reaction is allowed to proceed for a period of timeranging from about 30 minutes to about 24 hours. Preferably a timeperiod of from about 1 to 5 hours is employed, depending upon theparticular reactants, the solvent and temperature utilized. Suitabletemperatures range from -78° C. to 60° C., preferably about 20° C.Suitable solvents include ethereal solvents such as diethyl ether,tetrahydrofuran (THF), p-dioxane, 1,2-dimethoxyethane (DME), diglyme oran aromatic solvent such as benzene, toluene or xylene.

In general, the secondary nucleophilic amines of formula (2), wherein Xrepresents the radicals ##STR8## and R₂ is other than hydrogen, can beprepared by the direct alkylation of the corresponding primary aminewith a suitable alkyl halide, tosylate or mesylate in an appropriatesolvent, such as acetonitrile, in the presence of at least oneequivalent or an excess of an organic or inorganic base, such aspotassium carbonate.

Many of the cyano derivatives of formula (4) are known compounds.Alternatively, these compounds can be prepared in an analogous manner asdescribed below. Thus, for example, utilizing the same example aspreviously employed the compound ##STR9## wherein A and B are asdescribed above, is reacted with 2-bromo or preferably2-chloroacrylonitrile. Approximately, equimolar amounts of the formula(5) compound and the haloacrylonitrile are mixed with 2 or more molarequivalents of a base, such as potassium carbonate, in an appropriatesolvent. The reaction is allowed to proceed at a temperature rangingfrom 0° C. to the boiling point of the reaction mixture, for a periodranging from about 1 to 24 hours. Suitable solvents employed includedimethylformamide; dimethylsulfoxide; acetone; chlorinated hydrocarbons,such as carbon tetrachloride, chloroform or methylene chloride; etherealsolvents, such as diethylether, tetrahydrofuran (THF) or diglyme;aromatic solvents, such as benzene, toluene or xylene; or alcoholicsolvents, such as methanol or ethanol.

Where the symbols A and B represent different atoms, a mixture ofproducts will be obtained. These mixtures can be readily separated andpurified by methods commonly known to those skilled in the art, such asby chromatography on silica gel or fractional recrystallization.Furthermore, when the R₁ or R₂ substituents of a compound of formula (1)are hydroxy, the hydroxyl group must be protected prior to undergoingthe above described 2-bromo- or 2-chloroacrylonitrile condensationreaction. Suitable protecting groups include the benzyl or methylgroups. These protecting groups are subsequently removed to form thecorresponding nucleophilic amines represented by formula (2). Theremoval of such protecting groups can be by any suitable means generallyknown to the art, such as the catalytic reduction of the benzyl group,treatment with an acid such as hydrobromic acid, or treatment with borontribromide.

The compounds of formula (3) are essentially N-alkyl derivatives ofsaccharin. The leaving groups (L) for compounds of formula (3) canrepresent any group known to those skilled in the art, such as atosylate (OTS) or mesylate (OMS), an iodide, bromide or chloride, orhydroxyl group. Formula (3) substrates wherein L is a bromide or aniodide can be prepared by treating the corresponding dihaloalkane withone equivalent of the sodium salt of saccharin in an appropriate solventfor about one hour at a temperature of about 100° C., in accordance withthe following reaction scheme. ##STR10## wherein the symbol Halrepresents chloro, bromo or iodo.

Suitable solvents include dimethylformamide; dimethylsulfoxide; acetone;aromatic solvents, such as benzene, toluene or xylene; or an etherealsolvent, such as diethyl ether, tetrahydrofuran (THF) or1,2-dimethoxyethane (DME).

The compounds of formula (1) possess useful antianxiety andantihypertensive properties. Anxiolytic properties are suggested using5-HT_(1A) in vitro receptor binding studies, see Middlemiss et al., Eur.J. Pharmacol., 90, 151-3 (1983) and Glaser et al., Arch. Pharmacol.,329, 211-215 (1985). The antihypertensive effects of the compoundsdescribed herein can be determined both in the anesthetized normotensiverat and/or in the conscious spontaneously hypertensive rat in accordancewith the procedure of Fozard, J. Cardiovascular Pharm., 4, 829-838(1982).

The compounds of this invention can be administered either orally,subcutaneously, intravenously, intramuscularly, intraperitoneally orrectally. The preferred route of administration is oral. The amount ofcompound to be administered can be any effective amount, and will varydepending upon the patient, the mode of administration and the severityof the anxiety to be treated. Repetitive daily administration of thecompounds may be desirable, and will vary depending upon the patient'scondition and the mode of administration.

For oral administration, an anxiolytic or antihypertensive effectiveamount of a formula (1) compound can range from 0.005 to 10 mg/kg ofpatient body weight per day, preferably from 0.05 to 5 mg/kg of patientbody weight per day. The preferred antianxiety dose of the compounds offormula (1a) is about 0.1 mg/kg of patient body weight per day.Pharmaceutical compositions in unit dose form can contain from 1 to 50mg of active ingredient and can be taken one or more times per day.

For parenteral administration, an anxiolytic or antihypertensiveeffective amount of a formula (1) compound is from about 0.005 to 10mg/kg of patient body weight per day, preferably from about 0.05 to 5mg/kg of patient body weight per day. A parenteral composition in unitdose form can contain from 0.1 mg to 10 mg of active ingredient and canbe taken one or more times daily.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, lozenges, melts,powders, solutions, suspensions or emulsions. Solid dosage unit formsgenerally employed include capsules or tablets. Capsules can be of theordinary gelatin type which contain additional excipients such as,surfactants, lubricants and inert fillers such as lactose, sucrose andcornstarch. Additionally, the compounds of formula (1) can be tabletedwith conventional tablet bases such as lactose, sucrose, and cornstarchin combination with binders, such as acacia, cornstarch or gelatin,disintegrating agents such as potato starch or alginic acid, andlubricants such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or a suspension of the compound in aphysiologically acceptable diluent with or without a pharmaceuticalcarrier. Suitable diluents or carriers include sterile liquids such aswater or oils, with or without the addition of surfactants or otherpharmaceutically acceptable adjuvants. Illustrative of various oils thatcan be employed in the practise of this invention are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, and mineral oil. In general, water, saline, aqueousdextrose and related sugar solutions, ethanol and glycols such aspropylene glycol or polyethylene glycol are preferred liquid carriers,particularly for injectable solution.

The following examples illustrate the preparation of representativecompounds employed in the practice of this invention, but are notintended to limit the invention in any way thereto.

EXAMPLE I ##STR11##2-[4-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]butyl]-1,2-benzoisothiazol-3(2H)one-1,1-dioxideN-(4-Bromobutyl)saccharin

Saccharin (9.35 g, 50 mM) in 80 ml of N,N-dimethyl formamide (DMF) isadded to 55% sodium hydride (2.18 g, 50 mM) in 20 ml of dry DMF. After15 minutes, 1,4-dibromobutane (25 ml, 200 mM) is added rapidly, and themixture is warmed for 1 hour at 100° C. with stirring. The reactionmixture is cooled, filtered and the DMF is evaporated. The crude productis dissolved in methylene chloride and the solution is filtered, driedand evaporated, yielding a yellow oil which is purified bychromatography on silica gel (CH₂ Cl₂ /MeOH, 98/2) to afford 13.4 g(84%) of a colorless oil. This oil, when crystallized from isopropanol,yields N-(4-bromobutyl)saccharin having a melting point of 72° C.

NMR CDCl₃ /TMS 60 MHz 8.20-7.85 (m, 4H Ar), 4.00-3.30 (m, 4H), 2.40-180(m, 4H).

2-[4-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]butyl]-1,2-benzoisothiazol-3(2H)one-1,1-dioxidehydrochloride

2-Aminomethyl-benzodioxan[1,4] (0.965 g, 5.48 mM), potassium carbonate(3 g) and N-(4-bromobutyl)-saccharin (1.43 g, 4.5 mM), prepared asabove, are mixed in N,N-dimethylformamide (DMF, 10 ml). The mixture isstirred at 100° C. overnight, cooled, filtered and evaporated todryness. The residue is dissolved in ethyl acetate, washed with waterand acidified with dilute hydrochloric acid. The oil which separates iswashed with ether, 5% HCl, water, dissolved in methanol, dried andevaporated to dryness, affording 1.3 g of a crude yellow solid. Thismaterial is converted to the free base and flash-chromatographed onsilica (CH₂ CO₂ /MeOH 97/3), yielding 0.91 g of the desired compound.The hydrochloride salt is recrystallized from an isopropanol/ethylacetate solution to yield the title compound having a melting point of210° C.

Following essentially the same procedure but substitutingN-(2-bromoethyl)saccharin for the N-(4-bromobutyl)saccharin above, thecompound2-[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)-methylamino]ethyl]-1,2-benzoisothiazol-3(2H)one-1,1-dioxideis obtained, having a melting point of 181° C.

EXAMPLE II ##STR12##2-[4-(2-[1,2,3,4]-tetrahydro-β-carbolinyl)butyl]-1,2-benzoisothiazol-3(2H)one-1,1-dioxide

Following essentially the same procedure as in Example I, butsubstituting [1,2,3,4]-tetrahydro-β-carboline for2-aminomethyl-benzodioxan[1,4], the title compound was prepared andcrystallized as a hydrochloride, having a melting point of 272° C.

EXAMPLE III ##STR13##2-[4-[8-Methoxytetralin-2-amino]butyl]1,2-benzoisothiazol-3(2H)one-1,1-dioxide

Following essentially the same procedure as in Example I, butsubstituting 8-methoxy-2-aminotetralin for2-aminomethylbenzodioxan[1,4], the title compound was prepared andcrystallized as a hydrochloride, having a melting point of 233° C.

EXAMPLE IV ##STR14##2-[4-[5-Methoxy-indol-3-yl)ethylamino]butyl]1,2-benzoisothiazol-3(2H)one-1,1-dioxide

Following essentially the same procedure as in Example I, butsubstituting 5-methoxy-tryptamine for 2-aminomethyl-benzodioxan[1,4],the title compound was prepared and crystallized as a hydrochloride,which decomposes prior to melting.

1H NMR (free base, CDCl₃ +CD₃ OD, 360 MH_(z), ppm): 8.4 (1H, s), 8.0-7.7(4H, m), 7.2-6.75 (4H, m), 3.8 (3H, s), 3.8-3.6 (2H, m), 3.15 (4H, m),2.9 (2H, t), 1.85 (4H, m).

EXAMPLE V ##STR15##2-[4-[(2,3-Dihydro-1,4-benzoxazin-3-yl)methylamino]butyl]-1,2-benzoisothiazol-3(2H)one-1,1-dioxide

Following essentially the same procedure as in Example I, butsubstituting 2-aminomethylbenzoxazin for 2-aminomethylbenzodioxan[1,4],the title compound was prepared and crystallized as a hydrochloride,having a melting point of 209° C.

EXAMPLE VI In vitro Determination of Anxiolytic Properties via 5-HT_(1A)Binding

Radioligand binding studies of the 5-HT_(1A) recognition sites werecarried out as follows: male mormotensive Sprague-Dawley rat frontalcortex was dissected, frozen in liquid nitrogen and stored at -20° C.until needed. Tissues from 4-8 rats were pooled and homogenised in 70vol Tris-HCl buffer (50 mM, pH 7.7), using a kinematica Polytron(setting 2/3 max speed, 20 sec). The homogenate was centrifuged (36500×gfor 10 min), the pellet re-homogenised in the same volume of buffer andthe process repeated two more times. Between the second and thirdcentrifugations the tissue homogenate was incubated at 37° C. for 10min. The final pellet was suspended in the same volume of Tris buffercontaining 10M pargyline, 5.7 mM CaCl₂ and 0.1% ascorbic acid. Thissuspension was incubated for 10 min at 37° C. and then stored on iceuntil used in the binding assay.

Tissue homogenate (0.7 ml), radioactive ligand (0.1 ml) and theappropriate concentration of test compound (0.1 ml), together withbuffer to a final volume of 1 ml were incubated at 37° C. for 15 min.Incubations were terminated by rapid filtration through Whatman GF/Bfilters followed by three 5 ml washes with ice-cold Tris-HCl buffer (50mM, pH 7.0). Radio-activity was measured after extraction into Aquasol-Z(NEN) at an efficiency of 45-50%. The radioligand used to label the5-HT_(1A) recognition sites and its concentration is [³H]-8-hydroxy-2-(di-n-propylamino)-tetralin, ([³ H]-8-OH-DPAT), 1 mM.

Following essentially the above procedure, the following compounds weretested. Results are expressed as pIC₅₀ (log₁₀ concentration of testcompound which inhibits specific binding by 50%), and represent themeans ±S.E.M. of 3 independent experiments.

    ______________________________________                                                   5-HT.sub.1A Binding Affinity                                       Test Compound                                                                            Rat Brain Cortex *Fold Increase                                    ______________________________________                                        Buspirone  7.52 ± 0.10   1                                                 Example I(A)                                                                             9.34 ± 0.03   66                                                Example II 8.16 ± 0.07   4.4                                               Example III                                                                              8.52 ± 0.14   10                                                Example V  8.03 ± 0.15   3.2                                               ______________________________________                                         *Antilog of the difference of the test compound compared to buspirone    

As indicated in the above data, the compounds tested represent a 3 to 60fold increase in potency, based upon 5HT_(1A) binding studies, whencompared to buspirone.

EXAMPLE VII Determination of Antihypertensive properties

Male, normotensive Sprague-Dawley rats weighing 250-350 g (supplied byCharles River, France) were anesthetized with pentobarbitone sodium, 60mg/kg, i.p., plus 15 mg/kg s.c. Blood pressure was recorded either fromthe left common carotid artery or from a femoral artery by means of aStatham pressure transducer (Type P23 AA) and heart rate was recordedfrom the electrocardiogram using a Beckman cardiotachometer coupler(Type 9757 B). Records were displayed on a Beckman dynograph (Type R). Afemoral vein was cannulated for the intravenous injection of drugs.After completion of all operative procedures, heparin 500 U was injectedintravenously.

The compounds of Example I,2-[4-[(2,3-dihydro-1,4-benzodioxine-2-yl)methylamino]butyl]-1,2-benzoisothiazol-3(2H)one-1,1-dioxidewas administered s.c. as a saline solution in a volume of 1 ml/kg bodyweight. The following changes in blood pressure (B.P.) and heart rate(H.R.) were observed.

    ______________________________________                                        Dose        Δ BP (mmHg)                                                                         Δ HR (beats/min)                                ______________________________________                                        25 μg/kg -35         -80                                                   500 μg/kg                                                                              -50         -90                                                   ______________________________________                                    

In a separate experiment arterial blood pressure and heart rate weremeasured directly in conscious male, spontaneously hypertensive ratsweighing 250-350 g (Charles River, France). The same test compound wasadministered, either s.c. or orally, as a saline solution of 1 ml/kgbody weight in the doses shown below.

    ______________________________________                                        Route and Dose                                                                              Δ BP (mmHg)                                                                         Δ HR (beats/min)                              ______________________________________                                        100 μg/kg s.c.                                                                           -20         +80                                                 200 μg/kg s.c.                                                                           -65         +100                                                500 μg/kg s.c.                                                                           -75         +120                                                1 mg/kg per os.                                                                             -25         +100                                                5 mg/kg per os.                                                                             -45         +100                                                ______________________________________                                    

In short, under the conditions tested, it can be said that the compound,2-[4-[(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]butyl]1,2-benzoisothiazol-3(2H)one-1,1-dioxideeffectively lowers the blood pressure and heart rate in anesthetizednormotensive rats, and lowers the blood pressure with reflex tachycardiain conscious spontaneously hypertensive rats.

We claim:
 1. An aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivative havingthe formula ##STR16## wherein n is an integer of from 2 to 5; X is##STR17## wherein one of A and B is an oxygen and the other is NR'wherein R' is hydrogen or methyl; or a pharmaceutically acceptable acidaddition salt thereof.
 2. An aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivative ofclaim 1 wherein n is an integer of from 2 to
 4. 3. An aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivative ofclaim 1 wherein n is the integer
 4. 4. An aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivative ofclaim 1 wherein A is an oxygen and B is an NR'.
 5. An aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivative ofclaim 3 wherein n is an integer of from 2 to
 4. 6. An aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivative ofclaim 3 wherein n is the integer
 4. 7. An aromatic2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivative ofclaim 1 wherein A is an oxygen and B is an NR' wherein R' is hydrogen.8. An aromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxidederivative of claim 6 wherein n is an integer of from 2 to
 4. 9. Anaromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxidederivative of claim 6 wherein n is the integer
 4. 10. A method forrelieving the symptoms of anxiety in a patient in need thereof, whichcomprises the administration to said patient of an anxiolytic effectiveamount of a compound of one of claims 14-22.
 11. A method for loweringblood pressure in a person in need thereof, which comprises theadministration to said patient of an antihypertensive effective amountof a compound of one of claims 14-22.
 12. An anxiolytic compositioncomprising an anxiolytic effective amount of a compound according to oneof claims 14-22, or a pharmaceutically acceptable acid addition saltthereof, in combination with a pharmaceutically acceptable carrier ordiluent.
 13. An antihypertensive composition comprising anantihypertensive effective amount of a compound according to one ofclaims 14-22, or a pharmaceutically acceptable acid addition saltthereof, in combination with a pharmaceutically acceptable carrier ordiluent.